The purpose of this study is to evaluate the efficacy of addition of everolimus to letrozole with LHRH agonist in premenopausal metastatic breast cancer patients who failed to tamoxifen treatment.

Endocrine therapy is the cornerstone of treatment for patients with hormone receptor (HR)-positive advanced breast cancer. The selection of endocrine agents takes account of the menopausal status, the type of previous adjuvant endocrine treatment, the disease free interval and past medical history1.

The goal of endocrine treatment is to block or interfere with the function of estrogen or progesterone. The major source of estrogen in premenopausal women is the ovaries. In premenopausal women with HR-positive advanced breast cancer, tamoxifen, ovarian function suppression or a combination of those have been used. Unfortunately, not all patients have a response to first-line endocrine therapy, and even patients who have a response will eventually become resistant. Patients experiencing disease progression with a first-line endocrine therapy may benefit from other endocrine agents, such as aromatase inhibitors (steroidal or nonsteroidal) and the estrogen receptor (ER) antagonist2-5. Aromatase inhibitors combined with luteinizing hormone-releasing hormone (LHRH) analogs or ovarian ablation are also a feasible treatment modality for premenopausal patients with HR-positive advanced breast cancer6.

An emerging mechanism of endocrine resistance in aberrant signaling through the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway7-9. Growing evidence supports a close interaction between the mTOR pathway and ER signaling. A substrate of mTOR complex 1 (mTORC1), called S6 kinase 1, phosphorylates the activation function domain 1 of ER, which is responsible for ligand-independent receptor activation10. Everolimus is a sirolimus derivative that inhibits mTOR through allosteric binding to mTORC111. In preclinical models, the use of everolimus in combination with aromatase inhibitors results in synergistic inhibition of the proliferation and induction of apoptosis12. In a randomized, phase 2 study comparing neoadjuvant everolimus plus letrozole with letrozole alone in patients with newly diagnosed ER-positive breast cancer, the response rate for the combination was higher than that for letrozole alone13. Recently, the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study showed that the addition of everolimus to exemestane significantly improved progression-free survival, with observed medians of 6.9 and 2.8 months, corresponding to a 57% reduction in the hazard ratio14.

Based on this rationale, the investigators introduced randomized trial to evaluate the efficacy of addition of everolimus to letrozole with LHRH agonist in premenopausal metastatic breast cancer patients who failed to tamoxifen treatment.

Inclusion Criteria:

• Age ≥ 20 years
• Histologically or cytologically confirmed, HER-2 negative breast cancer with recurrent or metastatic disease
• No HER2 overexpressing breast cancer
• Premenopausal status, defined as either
• ER and/or PR positive
• Progressive disease on tamoxifen treatment or sequential or combined treatment of tamoxifen and GnRH agonist as a palliative or an adjuvant endocrine treatment
• Duration of tamoxifen treatment should be at least 3 months or more
• No prior treatment with an aromatase inhibitor or inactivator or fulvestrant, or mTOR inhibitors
• One line of chemotherapy in metastatic setting is permitted
• ECOG performance status 0,1 or 2
• At least one measurable lesion or mainly lytic bone lesions in the absence of measurable disease
• Adequate hematologic, liver and kidney function

Exclusion Criteria:

• Pregnant women or patients in lactation
• More than one line of prior chemotherapy for metastatic breast cancer
• GnRH agonist with tamoxifen treatment within 2 weeks.
• Active malignancy other than breast cancer, in situ carcinoma of the cervix, controlled resected thyroid well differentiated carcinoma or non-melanomatous skin cancer in the past 5 years
• Active cardiovascular disease such as angina, ventricular tachycardia, uncontrolled hypertension
• Active uncontrolled infection
• Symptomatic brain metastases
• Lymphangitic carcinomatosis involving >50% of the lungs
• Evidence of metastases involving more than one third of the liver on sonogram or CT
• Patients not able or unwilling to give informed consent